This is an application for a K23 Mentored Patient-Oriented Research Career Development Award. The overall goal of the proposal is to provide the candidate with critical skill sets and broad development of experience and competence as an independent, translational, clinician researcher. The candidate proposes a comprehensive training plan, combining didactic training by mentors with formal course work, and gaining experience in clinical research, to achieve the long-term goal of becoming an independent investigator with research focus on biomarker-based identification of early stages of neurodegenerative disease (e.g., AD) leading to targeted delirium prevention. Specific training goals include : (1) conducting a longitudinal study and advanced didactic training in analysis of longitudinal data, (2) in-depth understanding of perioperative risk factors and methodologies in assessment of delirium and functional status, (3) in-depth understanding of measurement and standardization issues related to CSF biomarkers and their association with neuropathology of non-demented subjects with AD pathology. The training goals will be executed in coordination with a specific set of research projects that are based upon the candidate's preliminary data which examines the association of CSF biomarkers of AD, amyloid-beta (A42) and tau (total tau and p-tau181) with the occurrence and severity of postoperative delirium, changes in function, and greater health care burden (longer hospital stay and level of care change) in patients without dementia who are undergoing hip fracture repair. In the preliminary data, lower CSF A42 and higher tau levels suggestive of underlying AD pathology were associated with more severe delirium, demonstrating that these patients may be more vulnerable to the stresses of anesthesia, surgery, and post-operative care, and delirium may be the clinical manifestation of underlying pathology. The proposed project will be incorporated into an on-going NIH funded project A Strategy for Reduction of Postoperative Delirium in Elderly Patients (R01 AG033615), a study of postoperative delirium in hip fracture repair patients. Cerebrospinal fluid (CSF) will be collected during spinal anesthesia from patients without dementia, and the association between CSF biomarkers of AD, amyloid-beta (A42) and tau (total tau and p- tau181) and the following will be examined: (1) occurrence and severity of postoperative delirium, (2) long-term functional outcomes at 1 and 6 months after surgery, (3) and length of hospital stay and level of care change ( e.g. from home to assisted living facility or nursing home placement) at 1 and 6 months after surgery. The results from this proposed project will demonstrate that postoperative delirium in older adults without dementia in part reflects early (preclinical, mild cognitive impairment) AD. This project will also lead to early identification of patients at high risk for postoperative delirium, and facilitate targeted delirium intervention. It may also lead to future studies where treatment of underlying AD in the early stages may result in lower incidence of delirium and better postoperative outcomes. PUBLIC HEALTH RELEVANCE: The purpose of this study is to find out if patients who are not demented, but who may have underlying brain disease consistent with Alzheimer's disease, may be at higher risk for becoming confused (delirium) after surgery. The findings from this study may lead to identification of high risk patients before surgery to minimize the risk of delirium.